Perivascular adipose tissue has been recognized unequivocally as a major player in the pathology of metabolic and cardiovascular diseases. Through its production of adipokines and the release of other thus far unidentified factors, this recently discovered adipose tissue modulates vascular regulation and the myogenic response. After the discovery of its ability to diminish the vessel's response to vasoconstrictors, a new paradigm established adipose-derived relaxing factor as a paracrine smooth muscle cells' potassium channel opener that could potentially help combat vascular dysfunction. This review will discuss the role of adipose-derived relaxing factor in vascular dysfunction in obesity and hypertension, the different potassium channels that can be activated by this factor, and describes new pharmacological tools that can mimic the adipose-derived relaxing factor effect and thus can be beneficial against vascular dysfunction in cardiovascular disease.